June 26, 2014: From Chemical Probes to Potential Therapeutics: This LOX Is No Fish Story

For basic research scientists, defining the role of a particular protein in health and disease — an early translational hurdle called “target qualification” — often is easier said than done. A chemical “probe” that can increase or decrease the activity of the target protein can be invaluable for target qualification. The problem is that creating these probes requires expertise in high-throughput (large-scale) screening and chemistry that most disease biologists lack. In these situations, collaboration across scientific disciplines is essential to moving research forward.

To meet this critical need, the NIH Chemical Genomics Center (NCGC), which is now part of NCATS, was established in 2004. NCGC was the first center in a network of small molecule screening and medicinal chemistry optimization sites that produced small molecule chemical probes as part of the NIH Common Fund’s Molecular Libraries Program.

Over the past decade, NCGC scientists have partnered with academic, nonprofit and biotech researchers on more than 300 probe development projects in virtually every area of biology and disease. NCGC is organized much like a biotechnology firm, including a collaborative project team structure and leading-edge tools and technologies. But NCGC scientists focus on the large universe of unexplored targets, thus leading to new approaches and complementing the work of private-sector partners.

NCGC staff work collaboratively with disease experts to develop research plans and produce biological assays (or tests), which are screened against hundreds of thousands of compounds using our state-of-the-art, high-throughput screening robots. In this way, investigators with a promising idea about important new biology or a novel way to reverse a disease state can access the scientific expertise, tools and resources required to test that idea. Innovative translational solutions like this one help speed the development of new treatments for patients and are at the core of NCATS’ mission.

Here’s a recent example of how our problem-solving potential can become a reality and exemplify the “NCATS 3Ds”: Three molecular probes developed in collaboration with our experts spurred work by multiple academic scientists that led to insights about the biology of several diseases. The probes act as inhibitors of various lipoxygenase (LOX) enzymes, which help the body break down fatty acids. The team, comprised of NCATS researchers and their collaborators, then demonstrated that these three small molecule LOX inhibitors have the potential to treat diabetes, stroke and thrombosis (a clot-forming condition). The scientists now have disseminated their findings through multiple publications and invited conference presentations, which has fueled renewed interest by the broader research community in the role LOX enzymes may play in numerous diseases.

This work already has improved our understanding of how this enzyme family functions in health and disease and could potentially lead to the development of new therapies for a variety of conditions. These are exactly the kinds of outcomes we strive for at NCATS in our quest to improve the process of transforming basic science knowledge into treatments for disease and improved human health.

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences